Pharmacological Research 172 (2021) 105784 Available online 22 July 2021 1043-6618/© 2021 Elsevier Ltd. All rights reserved. Review Cancer chemopreventive role of fsetin: Regulation of cell signaling pathways in different cancers Ammad Ahmad Farooqi a, * , Humaira Naureen b , Rabbia Zahid c , Lara Youssef d , Rukset Attar e , Baojun Xu f, * a Department of Molecular Oncology, Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan b Faculty of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan c Institute of Chemistry, University of Punjab, Lahore, Pakistan d Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand (UOB), Al-Kurah, Lebanon e Department of Obstetrics and Gynecology, Yeditepe University, Turkey f Food Science and Technology Programme, BNU-HKBU United International College, Zhuhai, China A R T I C L E INFO Keywords: Fisetin Cancer prevention Cell signaling pathway PI3K/AKT/mTOR Wnt/β-catenin TRAIL/TRAIL-R Chemical compounds studied in this article: Fisetin (PubChem CID: 5281614) Sorafenib (PubChem CID: 9826472) Carnosic acid (PubChem CID: 65126) Cabazitaxel (PubChem CID: 9854073) Necrostatin (PubChem CID: 2828334) ABSTRACT It is becoming progressively more understandable that pharmaceutical targeting of drug-resistant cancers is challenging because of intra- and inter-tumor heterogeneity. Interestingly, naturally derived bioactive com- pounds have unique ability to modulate wide-ranging deregulated oncogenic cell signaling pathways. In this review, we have focused on the available evidence related to regulation of PI3K/AKT/mTOR, Wnt/β-catenin, NF- κB and TRAIL/TRAIL-R by fsetin in different cancers. Fisetin has also been shown to inhibit the metastatic spread of cancer cells in tumor-bearing mice. We have also summarized how fsetin regulated autophagy in different cancers. In addition, this review also covers fsetin-mediated regulation of VEGF/VEGFR, EGFR, nec- roptosis and Hippo pathway. Fisetin has entered into clinical trials particularly in context of COVID19-associated infammations. Furthermore, fsetin mediated effects are also being tested in clinical trials with reference to osteoarthritis and senescence. These developments will surely pave the way for full-fedge and well-designed clinical trials of fsetin in different cancers. However, we still have to comprehensively analyze and fully un- lock pharmacological potential of fsetin against different oncogenic signaling cascades and non-coding RNAs. Fisetin has remarkable potential as chemopreventive agent and future studies must converge on the identifca- tion of additional regulatory roles of fsetin for inhibition and prevention of cancers. 1. Introduction The advancements in molecular genetics and biochemistry in the decades from 1940 to 1980 attracted wide-spread attention of re- searchers because of landmark discoveries. These pioneering research- works were further refned because of the development of scientifc methodologies such as retrotranscription and positional cloning. Furthermore, conventional Sanger sequencing enabled us to witness milestone scientifc achievements and helped researchers to uncover underlying mysteries. Following the clear blueprint of two characteris- tically unique categories of genes as "tumor suppressors" and "onco- genes" between the 1980s and the early years of the frst decade of the 21st century, many of the genomic loci encoding tumor suppressors and oncogenes were identifed. Cancer cells have a unique ability to resist apoptosis, maintain proliferative signaling (even in the absence of extracellular signaling), initiate invasion and metastasis, enable Abbreviations: PRAS40, Proline-rich Akt substrate; S6K, ribosomal S6 kinase; 4EBP, eIF4Ebinding protein 1; TSC2, Tuberous sclerosis complex-2; RAPTOR, Regulatory Associated Protein of mTOR; RICTOR, Rapamycin-Insensitive Companion of mTOR; LRP5/6, Low-density lipoprotein receptor-related proteins 5/6; DKK1, Dickkopf Wnt Signaling pathway inhibitor; SFRPs, secreted Frizzled-related proteins; WIF, Wnt inhibitory factor; FasL, Fas ligand; TRAIL, Tumor necrosis factor-related apoptosis-inducing ligand; XIAP, X-Linked Inhibitor of Apoptosis; SMAC, Second Mitochondria-derived Activator of Caspase; DIABLO, Direct IAP- Binding protein with Low pI; IRE1, Inositol-requiring enzyme-1; ATF4, activating transcription factor-4; PERK, protein kinase RNA-like ER kinase; VEGF, Vascular Endothelial Growth Factor; IKK, inhibitor of IκB kinase; TET, Ten-eleven translocation; ZAK, Leucine zipper-and sterile alpha Motif-containing Kinase; LATS1/ LATS2, large tumor suppressors. * Corresponding authors. E-mail addresses: Farooqiammadahmad@gmail.com (A.A. Farooqi), baojunxu@uic.edu.cn (B. Xu). Contents lists available at ScienceDirect Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs https://doi.org/10.1016/j.phrs.2021.105784 Received 22 May 2021; Received in revised form 4 July 2021; Accepted 20 July 2021